Cerebral infarction is a disease exemplified as a cause of stroke together with cerebral bleeding and subarachnoid hemorrhage. Cerebral infarction is a neurodegenerative disease in which arteriosclerosis of a brain blood vessel or obstruction of a brain blood vessel caused by thrombi brought therein stops blood flow ahead thereof to cease feeding of nutrients into brain cells and finally causes the death of nerve cells. In addition, even when a patient with cerebral infarction has escaped sudden death, it sometimes leaves serious secondary diseases such as hemiplegia and aphasia caused by functional disorder of nerve cells. In the treatment of cerebral infarction, it is considered in general that, after obstruction of the brain blood flow, blood flow must be restored before brain tissues cause irreversible changes and result in necrosis. On the other hand, it is considered that there is a therapeutic time window (hereinafter referred to as “TTW”) in cerebral infarction, within which cerebral infarction can be treated almost without leaving secondary diseases. Although the length of TTW is considered to differ in each case of the disease depending on the developing degree of collateral circulation, but is roughly 3 hours, or about 6 hours at the longest, after the stroke.
Examples of the currently and mainly used as cerebral infarction treating agents include thrombolytic agents such as tissue plasminogen activator (t-PA) and urokinase, anticoagulants such as warfarin and heparin, and free radical scavengers such as Radicut (edalabon) (product name: manufactured by Mitsubishi Pharma Corporation). However, t-PA shows its efficacy only when it is administered within 3 hours after onset of cerebral infarction, namely within TTW, and with respect to anticoagulants, since it takes several days to express the anticoagulation action, the effects could hardly be said to be sufficient. In addition, since Radicut (product name: manufactured by Mitsubishi Pharma Corporation) sometimes causes serious side effects such as nephropathy, its use requires sufficient precautions. Thus, since the currently used cerebral infarction treating agents have problems in terms of their effect or toxicity and also have many limitations regarding their use, the development of useful therapeutic agents has been desired earnestly.
Also, involvement of S-100 protein in various neurodegenerative diseases has been revealed in recent years. For example, it has been reported that measurement results of blood S-100 protein can be used in the diagnosis of cerebral lesions and neurological damages in stroke (Stroke, vol. 28, pp. 1956-1960 (1997)). It is known that S-100β, a kind of the S-100β protein, is a protein which is present at a high concentration in glial cells and Schwann cells in the central nervous system and peripheral nervous system and also in anterior pituitary cells and Langerhans cells. It is known that S-100β in cerebrospinal fluid or blood is increased by cerebral infarction, subarachnoid hemorrhage, head injury, various neurodegenerative diseases or a nervous complication after a heart-lung bypass operation.
On the other hand, it has been reported that (2R)-2-propyloctanoic acid, which has activity of reducing the intracellular S-100β content, has a potentiality to be used as an agent for the treatment or prevention of various cranial nerve diseases including stroke, through the improvement of the function of abnormally activated astrocyte (e.g., see Tateishi, N. and 8 others, Journal of Cerebral Blood Flow & Metabolism, 22(6), 723-734 (2002)).
Also, since pentanoic acid derivatives including (2R)-2-propyloctanoic acid have an action to improve functions of astrocyte, it is known that they are effective for treating stroke and other various diseases. In addition, it has been described that they are orally administered once to several times a day within a range of 1 to 1,000 mg per one dose per adult, or parenterally administered once to several times a day within a range of 0.1 to 100 mg per one dose (e.g., see the specification of European Patent No. 0632008).
Further, a method for treating a cerebral ischemic disease which comprises administering (2R)-2-propyloctanoic acid or a salt thereof in combination with thrombolytic agents such as a tissue plasminogen activator is known (e.g., see the specification of International Publication No. 03/007992).
However, the therapeutic method described in said patent documents are methods which are limited to parenteral administration of at most 100 mg of the compound per one administration. Particularly, it is not known that the compound can show its efficacy safely in patients by its parenteral administration at a dose of exceeding 100 mg per one administration.